Hepatic triglyceride lipases--effect of clofibrate and halofenate.

Liver lipases could be important for regulating hepatic intracellular triglyceride (TG) concentration and, thus, TG secretion. The possibility that the hypotriglyceridemic drugs clofibrate (CPIB) and halofenate (HFA) reduce hepatic net TG synthesis by stimulating hepatic lipases has been investigated in control and orotic acid fed rats. Liver lipase activities were measured at pH 5, 7.5 and 8.5 in liver homogenates from control and drug-treated animals. The acid lipase was particularly sensitive to changes in hepatic TG concentration, increasing when hepatic TG levels were increased by feeding orotic acid and decreasing after treatment with either HFA of CPIB, drugs which lower hepatic TG levels. Both CPIB and HFA prevented the fatty liver produced by orotic acid. Neither drug increased the activity of the hepatic lipases with triolein as substrate (at an enzyme-saturating concentration) and, thus, the abilities of HFA and CPIB to decrease hepatic net TG synthesis and to prevent orotic acid-induced fatty liver are not related to effects on these liver lipases. Rather, they may be related to reducing the availability of fatty acids for de novo TG synthesis. CPIB and HFA produced a 65–75 per cent decrease in plasma free fatty acid (FFA) concentrations and this decrease could be important since circulating free fatty acids are a principal source of the fatty acid needed for hepatic TG synthesis.     

The effect of therapeutic doses of paracetamol on liver function in the rat perfused liver

Abstract— The isolated liver perfusion technique was used to study the effect of therapeutic doses of paracetamol on hepatic gluconeogenesis and bromosulphthalein clearance from the perfusate and biliary excretion of the dye in the rat. Six groups of rats were studied; those in the three experimental groups were given 0·02 g kg^?1 paracetamol daily for ninety days. The livers of animals in the control group and in one of the experimental groups were perfused with a medium containing pyruvate. The animals in the second experimental and control group were perfused with a medium containing bromosulphthalein (10 mg/100 mL). The livers of the third experimental and control group were subjected to histological examination. The rate of glucose formation and glucose concentrations were decreased, while, lactate levels and lactate: pyruvate ratios were increased in paracetamol-treated rats. The mean concentration of bromosulphthalein in the perfusate and biliary excretion of the dye were decreased. Macro and micro vesicular fatty change was present in the livers of paracetamol-treated rats. This study demonstrates that chronic administration of therapeutic doses of paracetamol to rats adversely affects liver function, as evidenced by impaired gluconeogenesis and bromosulphthalein clearance from the perfusate, and excretion of the dye into the bile, and provides histological evidence of hepatic damage in rats.     

Clofibrate pharmacokinetics: effect of elevation of plasma-free fatty acids.

The pharmacokinetics of rho-chlorophenoxyisobutyrate (CPIB), the active metabolite of clofibrate were determined following intravenous administration in the rat. Serum CPIB concentrations were measured using an new TLC-GLC method. The results agree favourably with pharmacokinetics in human subjects after oral administration of clofibrate. Both clofibrate and free fatty acids (FFA) are extensively bound to circulating plasma proteins. When plasma FFA were elevated to about 2,000 muEq/1, the CPIB elimination half-life decreased form 19.3 h in controls to 7.3 h. Thus, elevation of FFA appears to significantly alter the pharmacokinetics of a highly bound drug.     

Effects of clofibrate on ethanol-induced modifications in liver and adipose tissue metabolism: role of hepatic redox state and hormonal mechanisms.

Mechanisms by which clofibrate decreases the development of acute alcoholic fatty liver were studied, especially in regard to hepatic redox state and hormonal regulation of carbohydrate and lipid metabolism. A partial inhibition of the ethanol-induced increase in cytosolic NADH/NAD ratio was observed. As a result, in clofibrate-treated rats hepatic α-GP concentration during ethanol oxidation also remained at the same level as in normal control rats. Clofibrate treatment prevented the ethanol-induced increase in the adipose tissue cAMP and plasma FFA concentrations. Hepatic concentrations of CoA-SH, acetyl-CoA and long chain acyl-CoA were markedly increased by clofibrate treatment. Plasma insulin concentration was decreased in clofibrate-treated rats, which also showed an impaired glucose tolerance. The results show that clofibrate is able to restrict the availability of substrates (α-GP and fatty acids) for hepatic triglyceride synthesis in vivo. In addition, it was concluded that the partial inhibition of ethanol-induced fatty liver by clofibrate may result from the enhancement of the oxidation pathway of fatty acid metabolism as suggested by the enormous increase in hepatic content of CoA-SH and its derivatives.     

Effect of clofibrate on the metabolism of oleate in the perfused rat liver

The effect of clofibrate on the metabolism of [1-¹⁴C]- and [U-¹⁴C]oleate was examined in the perfused rat liver. Clofibrate feeding severely reduced hepatic triglyceride secretion and enhanced ketone body production. The increase in the rate of incorporation of labeled tracers into perfusate oxidation products and ketone bodies due to the clofibrate treatment was demonstrated only with [U-¹⁴C]oleate. Clofibrate strongly reduced the rate of incorporation of oleate into perfusate triglyceride, whereas that into the phospholipid fraction of the post-perfused liver doubled. In consequence, the sum of the radioactivities in esterified lipids in the perfusate and the post-perfused liver was not altered by clofibrate. A clofibrate-dependent increase in phospholipid synthesis may restrict the amount of exogenous fatty acid which is available for the formation of triglyceride-rich lipoproteins.     

Papaverine-induced metabolic alterations in perfused canine and porcine liver

Papaverine was given to perfused porcine and canine livers to assess the effect of this antispasmodic on hepatic viability. Papaverine decreased oxygen consumption, portal venous resistance (PVR), and perfusate pyruvate while increasing perfusate lactate. After approximately 10 min, these parameters, except for perfusate lactate, began to return to their pre-papaverine values. The reduction of oxygen consumption accompanied by the output of lactate indicated a shift to anaerobic metabolism resulting from papaverine administration. These phenomena occurred in both species even though the reduction in PVR was much less pronounced in the porcine liver. The decrease in perfusate pyruvate was found to depend on pre-existing levels of pyruvate in the perfusate; the equations governing this behavior were similar in the canine and porcine livers. There was no correlation between change in lactate output and initial values of lactate; however, the change in perfusate lactate could be correlated to the change in perfusate pyruvate. Thus, the changes in pyruvate and lactate occurring upon papaverine administration are related to initial perfusate pyruvate, the levels of which may reflect the redox state of the hepatocytes. Papaverine did not improve the perfusion characteristics of porcine livers other than to slightly decrease PVR. Irreversible outflow block could be prevented or delayed by papaverine in canine preparations, however, when this drug was given at the onset of PVR rise. Thus, papaverine may be effective in perfusion and preservation of canine livers and other organs which undergo phenomena similar to outflow block due to venous sphincters.     

The role of the hepatocellular redox state in the hepatic triglyceride accumulation following acute ethanol administration

The role of the increased hepatocellular redox-state [( NADH]/[NAD+] ratio) as a mechanism underlying hepatic triglyceride deposition after acute ethanol dosing has been investigated in the rat. Following a single dose of ethanol (2 g/kg i.p.) in fasted rats, increases were observed at 1.5 hr in the hepatic [lactate]/[pyruvate] (133%), [3-hydroxybutyrate]/[acetoacetate] (69%) ratios, and the liver triglyceride concentration (129%). At the same time point, ethanol increased radioactivity incorporated into hepatic total lipid and triglyceride, after an injection of [U-14C] palmitic acid, by 76% and 158% respectively. Treatment of animals with Naloxone hydrochloride (2 mg/kg i.p.) at 1.0 hr and 2.5 hr after ethanol abolished these ethanol-mediated redox-state changes, without inhibiting ethanol oxidation or affecting hepatic acetaldehyde levels. This, however, did not prevent completely the triglyceride accumulation in the liver or reverse the enhanced uptake of radio-labelled palmitate caused by ethanol. Administration of sorbitol (3.5 g/kg i.p.) caused 109%, 57% and 200% increases in the hepatic [lactate]/[pyruvate], [3-hydroxybutyrate]/[acetoacetate] ratios and glycerol-3-phosphate concentrations respectively. However, the hepatic triglyceride concentration and the incorporation of [U-14C] palmitic acid into hepatic lipids were not influenced by this treatment. In vitro studies in which rat liver slices were incubated with [1-14C] palmitic acid also indicated that the altered [NADH]/[NAD+] ratio was not responsible for the decreased rate of fatty acid oxidation seen after ethanol administration or after the addition of ethanol to the incubation medium. In conclusion, these experiments indicate that increases in the hepatic [NADH]/[NAD+] ratio resulting from ethanol oxidation may not be directly implicated in the altered hepatic fatty acid utilisation and triglyceride deposition observed after acute ethanol administration in rats.     

Effect of increased cardiac output on liver blood flow,oxygen exchange and metabolic rate during longterm endotoxin-induced shock in pigs

1. We investigated hepatic blood flow, O₂ exchange and metabolism in porcine endotoxic shock (Control, n=8; Endotoxin, n=10) with administration of hydroxyethylstarch to maintain arterial pressure (MAP)>60 mmHg.
2. Before and 12, 18 and 24 h after starting continuous i.v. endotoxin we measured portal venous and hepatic arterial blood flow, intracapillary haemoglobin O₂ saturation (Hb-O₂%) of the liver surface and arterial, portal and hepatic venous lactate, pyruvate, glyercol and alanine concentrations. Glucose production rate was derived from the plasma isotope enrichment during infusion of [6,6-²H₂]-glucose.
3. Despite a sustained 50% increase in cardiac output endotoxin caused a progressive, significant fall in MAP. Liver blood flow significantly increased, but endotoxin affected neither hepatic O₂ delivery and uptake nor mean intracapillary Hb-O₂% and Hb-O₂% frequency distributions.
4. Endotoxin nearly doubled endogenous glucose production rate while hepatic lactate, alanine and glycerol uptake rates progressively decreased significantly. The lactate uptake rate even became negative (P<0.05 vs Control). Endotoxin caused portal and hepatic venous pH to fall significantly concomitant with significantly increased arterial, portal and hepatic venous lactate/pyruvate ratios.
5. During endotoxic shock increased cardiac output achieved by colloid infusion maintained elevated liver blood flow and thereby macro- and microcirculatory O₂ supply. Glucose production rate nearly doubled with complete dissociation of hepatic uptake of glucogenic precursors and glucose release. Despite well-preserved capillary oxygenation increased lactate/pyruvate ratios reflecting impaired cytosolic redox state suggested deranged liver energy balance, possibly due to the O₂ requirements of gluconeogenesis.

     

Dietary clofibrate stimulates the formation and size of estradiol-induced breast tumors in female August-Copenhagen Irish (ACI) rats

Administration of 0.4% clofibrate in the diet stimulated estradiol (E(2))-induced mammary carcinogenesis in the August-Copenhagen Irish (ACI) rat without having an effect on serum levels of E(2). This treatment stimulated by several-fold the NAD(P)H-dependent oxidative metabolism of E(2) and oleyl-CoA-dependent esterification of E(2) to 17beta-oleyl-estradiol by liver microsomes. Glucuronidation of E(2) by microsomal glucuronosyltransferase was increased moderately. In contrast, the activity of NAD(P)H quinone reductase 1 (NQO1), a representative monofunctional phase 2 enzyme, was significantly decreased in liver cytosol of rats fed clofibrate. Decreases in hepatic NQO1 in livers of animals fed clofibrate were noted before the appearance of mammary tumors. E(2) was delivered in cholesterol pellets implanted in 7-8-week-old female ACI rats. The animals received AIN-76A diet containing 0.4% clofibrate for 6, 12 or 28 weeks. Control animals received AIN-76A diet. Dietary clofibrate increased the number and size of palpable mammary tumors but did not alter the histopathology of the E(2)-induced mammary adenocarcinomas. Collectively, these results suggest that the stimulatory effect of clofibrate on hepatic esterification of E(2) with fatty acids coupled with the inhibition of protective phase 2 enzymes, may in part, enhance E(2)-dependent mammary carcinogenesis in the ACI rat model.     

Biopharmaceutics: Drug Metabolism and Pharmacokinetics: The Effect of Protein Binding on the Hepatic First Pass of O-Acyl Salicylate Derivatives in the Rat

In this work the in-situ perfused rat liver has been used to examine the effect of changing the protein content of the perfusate on the hepatic extraction of O-acyl esters of salicylic acid. The hepatic availability (F) of these solutes was studied at a flow-rate of 30 mL min^?1 with perfusate albumin concentrations of 0, 2, and 4% w/v. The hepatic availability of the esters was shown to decrease with increasing carbon-chain length in the O-acyl group; for all the esters the hepatic availability increased with increasing albumin concentration in the perfusate. The dispersion-model-derived efficiency number (R_N) of the esters was shown to increase with increasing lipophilicity and decrease with increasing albumin concentration in the perfusate. The unbound fraction (f_u) of the esters decreased with lipophilicity. R_N/f_u for acetylsalicylic acid remained relatively constant as the albumin concentration was increased. However, R_N/f_u for n-pentanoyl-and n-hexanoylsalicylic acids increased significantly as albumin concentration increased from 0% to 4%. Thus, for the more lipophilic solutes (n-pentanoyl- and n-hexanoylsalicylic acids) the presence of albumin apparently facilitates the uptake of unbound solute relative to acetylsalicylic acid.     

Metabolism of ethanol and sorbitol in clofibrate-treated rats

The rates of ethanol and sorbitol removal and the cytoplasmic and mitochondrial redox states of the liver were determined in female rats pretreated with clofibrate (ethyl-α-p-chlorophenoxyiso-butyrate) for 2–15 days. The drug significantly increased the rate of elimination of ethanol even within the first two days. A significant increase in liver mass took place within a week but cannot explain the initial increase in ethanol removal. Although the liver mass was increased by clofibrate, the rate of sorbitol removal was significantly decreased. A decrease in liver sorbitol dehydrogenase activity was also observed. The sum of the removal of ethanol and sorbitol, when they were simultaneously metabolized, was significantly decreased in clofibrate-treated rats as compared with control ones. Sorbitol inhibition of ethanol elimination was increased but ethanol inhibition of sorbitol elimination was abolished by clofibrate administration. Ethanol and sorbitol caused similar changes in cytoplasmic (lactate/pyruvate) and mitochondrial (β-OH-butyrate/acetoacetate) redox states of clofibrate-treated rat liver, as has been earlier observed in livers of control animals.     

Anti-hyperlipidemic effect of iodine eggs: studies on the mechanism of its action

The anti-hyperlipidemic effect of the iodine egg was found to be in the neutral lipid (NL) fraction in its yolk. For the purpose of clarifying the hypolipidemic effect of the iodine-containing NL fraction, the effect of clofibrate (CPIB) was investigated. CPIB was found to lower TC, atherogenic index [(TC-HDL cholesterol)/HDL cholesterol], TG and FFA, but not FC; while NL lowered TC, FC and the atherogenic index, but not TG and FFA. Cholesterol metabolites, probably metabolized in the liver, were examined. Hepatic cholesterol level was increased by NL and CPIB. The ratio of fecal bile acid of the excretion type, lithocholic acid (LCA) to deoxycholic acid (DCA), increased when NL and CPIB were administered, but the hepatic HMG-CoA reductase activity, responsible for the endogenous cholesterol synthesis, was not altered. Thus, the anti-hyperlipidemic mechanism of NL may be the mobilization of peripheral cholesterol to the liver, probably for the disposal by excretion as bile acids.     

Influence of some biological pyrimidines on the succinate cycle during and after cerebral ischemia

Some cortical metabolites (glycogen, glucose, glucose-6-phosphate, pyruvate, lactate, α-ketoglutarate, succinate, fumarate. malate, citrate, glutamate, glutamine, alanine, NH₄⁺) were studied in rat brain after 5 min of complete compression ischemia, as well as after 15 min of recirculation following 5 min of ischemia. These two conditions (ischemia and post ischemia restitution) were induced in control animals and in rats pretreated 1 hr before by an intraperitoneal injection of 120 mg·kg^?1 of some biological pyrimidines (uridine, cytidine and uridine disphosphate glucose).At the cerebral level total complete ischemia induced the: (a) drop of substrates and of glycolytic intermediates, consistent with the increase of lactate and redox state; (b) increase of succinate and alanine; (c) decrease of malate and fumarate; and (d) depletion of α-ketoglutarate. Some of these events may be regarded as the expression of the activation of the succinate cycle which contributed by approx. 10 per cent to the release of anaerobic energy during cerebral ischemia. Pretreatment with the tested pyrimidines did not modify this cerebral biochemical pattern.During post-ischemic recovery, cerebral parameters tended to normalize, except for a further increase in alanine production (as an expression of the activation of the alanine aminotransferase reaction) with conversion of pyruvate into α-ketoglutarate available for the ammonia-detoxicating processes (amination to glutamate and amidation to glutamine). During post-ischemic recovery, pretreatment with cytidine was poorly active. Pretreatment with uridine decreased glucose, glucose-6-phosphate and pyruvate cerebral concentrations, while succinate and alanine were increased. This latter effect was also present in the case of pretreatment with uridine diphosphate glucose. However, this substance increased the cerebral concentration of glycogen and decreased those of fumarate and malate. The different biochemical actions of uracyl derivatives are discussed with regard to their biological effects.     

Inhibitory effect of 5-hydroxytryptamine on lipogenesis in rat adipose tissues

5-Hydroxytryptamine (5-HT) inhibited the incorporation of ¹⁴C from ¹⁴C-labelIed glucose, pyruvate, citrate and acetate into fatty acids but it did not inhibit the conversion of ¹⁴C from citrate and acetate into CO 2 , and the citrate conversion into glyceride-glycerol in epididymal and mesenteric adipose tissue from 24h-fasted rats. 5-HT stimulated the formation of lactate from glucose and pyruvate, and increased the ratio of lactate produced/pyruvate taken up. This ratio was similar to the NADH:NAD ratio. These results indicate that 5-HT inhibits fatty acid synthesis in rat white adipose tissue by mechanisms similar to those of the catecholamines.     

Clofibrate disposition in renal failure and acute and chronic liver disease

Summary The disposition of clofibrate over 96 hours was observed following single oral dose in six patients with acute viral hepatitis, six patients with liver cirrhosis, seven patients with renal insufficiency, and six control subjects. No parameter of the disposition of CPIB (active form of clofibrate) was significantly altered in acute hepatitis. In liver cirrhosis, the mean plasma half-life was unchanged compared to controls (20.9 vs. 17.5 h), but plasma clearance of the non-protein bound drug was reduced (115 vs. 243 ml×min^–1), plasma protein binding was reduced (92.8 vs. 97.2 percent), and the apparent volume of distribution was increased (0.20 vs. 0.141×kg^–1). In renal insufficiency plasma half-life was prolonged 2 to 6-fold, depending on the degree of renal impairment. Total plasma clearance (3.4 vs. 7.1 ml×min^–1) and plasma clearance of the unbound drug (81 vs. 243 ml×min^–1 were reduced in patients with renal failure, the clearance of the unbound drug being inversely correlated with the serum creatinine concentration. Renal failure was also associated with decreased protein binding and an increased volume of distribution of CPIB, and with reduced urinary excretion of CPIB and its glucuronide metabolite. The dose of clofibrate should be halved in patients with cirrhosis. In renal insufficiency, the dose should be adjusted according to the individual serum creatinine level: only 10 to 15% of the usual weekly dose should be given in complete renal failure.     

Effect of chronic clofibrate administration on mitochondrial fatty acid oxidation.

The effect of chronic clofibrate administration on fatty acid oxidation by isolated liver and skeletal muscle mitochondria was studied to determine if the hypolipidemic action of clofibrate may be mediated by reducing levels of fatty acyl substrates via enhanced fatty acid oxidation. Oxygen consumption and CO₂ production associated with the oxidation of fatty acids were decreased 30 per cent in liver mitochondria from clofibrate-treated rats. By contrast, CO₂ production from acetate and citric acid cycle intermediates was not significantly affected. This indicates impairment of β-oxidation of fatty acids to the level of acetyl CoA, an interpretation supported by the findings of a decrease in ketone body production. In liver mitochondria, oxygen consumption associated with the oxidation of glutamate, succinate and ascorbate was depressed. The per cent decrease was comparable in the absence or presence of ADP or dinitrophenol, suggesting impairment of the respiratory chain. There was no effect on energy production or utilization, as evidence by unchanged respiratory control, ADP/O ratio, ATP?³²P exchange reaction, and substrate- or ATP-supported Ca²⁺ uptake. Unlike isolated liver mitochondria, there were no effects on oxygen uptake or fatty acid oxidation by muscle mitochondria. It is unlikely that the hypolipidemic effects of clofibrate are mediated by reducing fatty acyl substrate levels via enhanced fatty acid oxidation.     

Induction of peroxisomal fatty acyl-CoA oxidase and microsomal laurate hydroxylase activities by beclobric acid and two metabolites in primary cultures of rat hepatocytes

Beclobrate [2-(4-[(4-chlorophenyl)methyl]phenoxy)-2-methylbutyric acid ethyl ester], a structural analog of clofibrate, is used clinically as a lipid-lowering agent. Although, like clofibrate, beclobrate produces a profound hepatomegalic response in rodents, no studies of this drug on hepatic peroxisome proliferation have appeared. We have examined, relative to clofibric acid (CPIB), the concentration-dependent effects of beclobric acid (Beclo), the activity moiety of beclobrate, and two oxidized metabolites [a carbinol (M2) and a benzophenone (M3)] on peroxisomal fatty acyl-CoA oxidase (FACO) and microsomal laurate hydroxylase (LH) activities in primary cultures of rat hepatocytes. All compounds induced FACO and LH activities in a concentration-dependent manner after a 72 hr incubation with the cultured cells. Beclo was 4.8- and 6.5-fold more potent than CPIB as an inducer of FACO and LH respectively. M2 and M3 were more potent than Beclo as inducers of FACO and LH. Additionally, all compounds produced significant elevations relative to untreated control cultures in cellular lactate dehydrogenase activity (1.6- to 2.2-fold). We conclude that (1) Beclo is more potent than CPIB as an inducer of peroxisome proliferation-associated enzyme activities; (2) two metabolites of Beclo are more potent than the parent molecule as inducers of these activities and (3) these metabolites may contribute to the lipid-lowering and/or hepatomegalic effects of beclobrate in rats.     

Modification of intracellular glucose metabolism in human skin fibroblast preincubated with p-chlorophenoxyisobutyrate.

1. The effect of p-chlorophenoxyisobutyrate (CPIB) on glucose metabolism human skin fibroblasts was examined. 2. CPIB increased the incorporation of 2-deoxy-D-[U-14C]glucose into skin fibroblasts. 3. CPIB decreased [14C]CO2 production from D-[U-14C]glucose but did not affect pyruvate dehydrogenase activity. 4. CPIB reduced fatty acid oxidation activity and cholesterol synthesis but increased triglyceride synthesis. 5. These effects of CPIB were observed both in the presence and in the absence of insulin. 6. One possible mechanism of CPIB on reducing plasma glucose may be due to the increase of glucose incorporation into the cells and triglyceride synthesis in the cells.     

Vergleichende ultrastrukturell-morphometrische Untersuchung zwischen der Leberparenchymzelle der Wistarratte (Rattus norvegicus) und der Wüstenratte (Meriones crassus) nach einer einmaligen CPIB (Clofibrat)-Verabreichung

Summary Male Wistar (rattus norvegicus) and desert rats (meriones crassus) were given a single dose of 200 mg/kg of clofibrate (CPIB) p.o. and liver tissue was analysed by ultrastructural morphometry. CPIB induced a biphasic reaction pattern of hepatocellular organelles both in Wistar and desert rats. In the initial phase (2–5 h) the volume share of mitochondria per hepatocyte increased in both strains. In the hepatocytes of desert rats the total number of mitochondria increased whereas the volume of the single mitochondrium remained constant. In contrast, in Wistar rats the volume of the single mitochondrium showed a threefold increase. In the initial phase the number of microbodies both in Wistar and desert rats decreased, but the single volume doubled.The smooth endoplasmic reticulum of Wistar and of desert rats showed a smaller surface per hepatocyte after CPIB application. The surface of the rough endoplasmic reticulum per hepatocyte increased in Wistar rats and decreased in desert rats. In the late phase (5–12 h) the pattern of hepatic organelles returned to normal.

     

Adaptive changes in fatty acid profile of erythrocyte membrane in relation to plasma and red cell metabolic changes in chronic alcoholic men

Chronic alcohol consumption is a major reason for several human diseases, and alcoholism has been associated with a variety of societal problems. Changes in fatty acid metabolism in alcoholics and its effects leading to membrane damage are largely unknown. Therefore, we aimed to investigate the fatty acid composition of erythrocyte membrane phospholipids in relation with plasma lipid profile and other plasma metabolites in chronic alcoholics in comparison with controls. We systematically measured the levels of glucose, lactate and pyruvate in the blood and free amino acids, free fatty acids, mucoproteins and glycolipids, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein (VLDL) cholesterol and triglycerides (TG) in plasma of chronic alcoholics and controls. Furthermore, we measured fatty acid composition by gas chromatographic analysis. The fatty acid composition clearly revealed certain changes in chronic alcoholic erythrocyte membrane, chiefly increments in C16:0 and a decrease in C22:4 and C22:6 fatty acids besides the presence of unidentified fatty acids, probably C-24 or C-26 fatty acids. In addition, a significant increase in blood lactate, decrease in blood pyruvate and increased levels of free amino acids and free fatty acids, mucoproteins, VLDL cholesterol, TG and HDL-C in chronic alcoholics were observed with no significant change in plasma TC, LDL-C and glycolipids when compared with controls. Alcohol-induced alterations in plasma and erythrocyte membranes of chronic alcoholics in the present study might be an adaptive response to counteract the deleterious effects of alcohol. The implications of our findings warrant further investigation and needs further in-depth study to explore the mechanisms of alcohol-induced membrane changes.